Figure 1.

Graphical illustration of Mendelian randomization (MR) analysis. Arrows or dot lines represent the presence or absence of associations, respectively. The MR analysis estimates the causal effect of birth weight to adult disease risk in the presence of various measured and unmeasured confounding factors by carefully selecting single nucleotide polymorphisms (SNPs) that are associated with birth weight to serve as instrumental variables. Valid MR requires these selected SNPs to satisfy three conditions: selected SNPs are strongly associated with birth weight (condition i); selected SNPs are not associated with any known or unknown confounders that are associated with both birth weight and disease (condition ii); selected SNPs are independent of adult disease conditional on birth weight (condition iii). Note that the effects of instrumental variables (G) on the exposure of interest (x) may be indirect and mediated through mediator variables. Exemplary traits include BMI (body mass index), T2D (type 2 diabetes), and CAD (coronary artery disease). The notations in the figure are defined further in Text S4.